System and method for biological specimen mounting

ABSTRACT

A system and method for mounting a section onto a substrate, the system comprising: a fluid channel including: a fluid channel inlet that receives the section, processed from a bulk embedded sample by a sample sectioning module positioned proximal the fluid channel inlet, a section-mounting region downstream of the fluid channel inlet, and a fluid channel outlet downstream of the section-mounting region; a reservoir in fluid communication with the fluid channel outlet; and a manifold, fluidly coupled to the reservoir, that delivers fluid from the reservoir to the fluid channel inlet, thereby transmitting fluid flow that drives delivery of the section from the fluid channel inlet toward the section-mounting region.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. patent applicationSer. No. 14/706,479, filed 7 May 2015, which is a continuation of U.S.patent application Ser. No. 14/574,210, filed 17 Dec. 2014, now issuedas U.S. Pat. No. 9,041,922, which claims the benefit of U.S. ProvisionalApplication Ser. No. 61/917,219, filed 17 Dec. 2013 and U.S. ProvisionalApplication Ser. No. 62/034,935, filed 8 Aug. 2014, which are eachincorporated in its entirety herein by this reference. This applicationis also a continuation of co-pending U.S. patent application Ser. No.14/706,479, filed 7 May 2015, which is a continuation of U.S. patentapplication Ser. No. 14/574,217, filed 17 Dec. 2014, now issued as U.S.Pat. No. 9,057,671, the entirety of which is incorporated herein by thisreference.

TECHNICAL FIELD

This invention relates generally to the biological research field, andmore specifically to a new system and method biological specimenmounting.

BACKGROUND

It is commonly desirable in biological laboratories to mount tissuesections, or ‘specimens’, to slides for purposes of examining the tissuesections using a microscope, treating the tissue sections with a stainor dye, and for other purposes. As shown in FIG. 1, conventional systemsand methods for mounting specimens onto slides comprise placing tissuesections in a sufficiently deep water bath, with the specimens floatingon the surface of the water. The broad side of a slide is then rested onthe rim of the water bath and the slide is angled down into the waterback such that the slide is partially submersed in the water.Subsequently, a small brush or glass capillary tube is used tomanipulate a tissue section onto the slide. Typically, the slide isgradually drawn out of the water as additional tissue sections arearranged on the slide. In another variation of a conventional method,tissue is embedded in paraffin wax, sliced with a microtome, and thenselected sections of the embedded tissue are transferred to a heatedwater bath. The hot water bath partially melts the paraffin about thespecimens, and a glass slide treated with adherents is then used toscoop the tissue sections out of the hot water bath. Conventionalmethods of mounting specimens on slides are thus difficult,time-consuming, and labor-intensive.

There is thus a need in the biological research field for a new systemand method for biological specimen mounting. This invention providessuch a new system and method.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a schematic of an embodiment of a system for mounting asection to a substrate;

FIG. 2 depicts an example of a sample sectioning module interfacing witha system for mounting a section to a substrate;

FIGS. 3A-3C depict variations of a portion of a fluid channel in anembodiment of a system for mounting a section to a substrate;

FIGS. 4A-4C depict variations of elements configured to separateadjoining sections in an embodiment of a system for mounting a sectionto a substrate;

FIG. 5 depicts an example of a system for mounting a section to asubstrate;

FIG. 6A depicts an example of a portion of a system for mounting asection to a substrate;

FIG. 6B depicts a portion of an example of a system for mounting asection to a substrate;

FIG. 7 depicts a variation of a junction in a fluid channel, in anembodiment of a system for mounting a section to a substrate;

FIGS. 8 and 9 depict cross sectional views of variations of a portion ofa system for mounting a section to a substrate;

FIG. 10 depicts variations of sidewall configurations in an embodimentof a system for mounting a section to a substrate;

FIG. 11 depicts a variation of a manifold in an embodiment of a systemfor mounting a section to a substrate;

FIG. 12 depicts a variation of a manifold in an embodiment of a systemfor mounting a section to a substrate;

FIGS. 13A-13C depict phases of an example workflow implemented by anembodiment of a system for mounting a section to a substrate;

FIG. 14 depicts example portions of a substrate and section in anembodiment of a system for mounting a section to a substrate;

FIG. 15 depicts a schematic of an embodiment of a system for mounting asection to a substrate;

FIG. 16 depicts a portion of an embodiment of a system for mounting asection to a substrate;

FIGS. 17A-17C depict configurations of variations of an injector in anembodiment of a system for mounting a section to a substrate;

FIG. 18 depicts an additional variation of a wrinkle removal module inan embodiment of a system for mounting a section to a substrate;

FIG. 19 depicts different configurations of a wrinkle removal module andsubstrate in an embodiment of a system for mounting a section to asubstrate;

FIG. 20 depicts an additional variation of a wrinkle removal module inan embodiment of a system for mounting a section to a substrate;

FIG. 21 depicts an additional variation of a wrinkle removal module inan embodiment of a system for mounting a section to a substrate;

FIGS. 22A-22D depict phases of an example workflow implemented by anembodiment of a system for mounting a section to a substrate andremoving wrinkles from the section;

FIG. 23 depicts an embodiment of a system for mounting a section to asubstrate;

FIG. 24 depicts alternative examples of elements in an embodiment of asystem for mounting a section to a substrate;

FIG. 25 depicts portions of adjoined sections in an embodiment of asystem for mounting a section to a substrate;

FIG. 26 depicts an alternative variation of a fluid channel in anembodiment of system for mounting a section to a substrate;

FIG. 27 depicts a flow chart of an embodiment of a method for mounting asection to a substrate;

FIG. 28 depicts variations of a portion of an embodiment of a method formounting a section to a substrate;

FIG. 29 depicts variations of a portion of an embodiment of a method formounting a section to a substrate;

FIG. 30 depicts variations of a portion of an embodiment of a method formounting a section to a substrate;

FIG. 31 depicts variations of a portion of an embodiment of a method formounting a section to a substrate; and

FIG. 32 depicts variations of a portion of an embodiment of a method formounting a section to a substrate.

DESCRIPTION OF THE EMBODIMENTS

The following description of preferred embodiments of the invention isnot intended to limit the invention to these embodiments, but rather toenable any person skilled in the art to make and use this invention.

1. System

As shown in FIG. 1, an embodiment of a system 100 for coupling a section101 to a substrate 102 comprises: a fluid channel 110 having a fluidchannel inlet 120 that receives the section 101, processed from a bulkembedded sample by a sample sectioning module 103 positioned proximalthe fluid channel inlet 120, a section-mounting region 130 downstream ofthe fluid channel inlet, and a fluid channel outlet 140 downstream ofthe section-mounting region; a reservoir 150 in fluid communication withthe fluid channel outlet; and a manifold 160 fluidly coupled to thereservoir, that delivers fluid from the reservoir to the fluid channelinlet, thereby transmitting fluid flow that drives delivery of thesection from the fluid channel inlet toward the section-mountingreservoir. In some embodiments, the system 100 can additionally oralternatively include any one or more of: a filter 170, fluidlyconfigured between the fluid channel outlet and the manifold, thatprevents undesired substances from flowing into the fluid channel inlet;a temperature regulating module 180 in contact with fluid from thereservoir, that adjusts a temperature of fluid within the fluid channel;and a substrate actuation module 190 that transmits the substrate intothe section-mounting region in a first operation, and delivers thesubstrate from the section-mounting region, with the section mounted tothe substrate, in a second operation.

The system 100 functions to automate processing of sections (e.g.,histological specimen sections, biological sections, etc.) in a mannerthat consistently generates high-quality mounted sections, with minimalor no effort from a human technician. As such, the system 100 cansignificantly reduce labor-intensive aspects of mounting sections tosubstrates. The system 100 is preferably configured to implement atleast a portion of the method 200 described in Section 2 below.

In one specific workflow, the system 100 is configured to retrieve athin tissue section (e.g., generated from a microtome blade), toseparate the tissue section from a preceding section, to transport thesection to a microscope slide via a fluidic channel, and then to mountthe section onto the microscope slide with a substrate actuation modulethat coordinates movement of the microscope slide in relation to motionof the tissue section within the fluidic channel. In mounting a tissuesection onto the microscope slide, the geometry of the fluidic channelis configured to deliver the tissue section toward an interface at whichthe microscope slide and the surface of fluid within the fluidic channelintersect, center the tissue section onto the microscope slide, andorient the tissue section such that its sides are parallel to long edgesof the microscope slide. Mounting, in the specific workflow, is thenconsummated by causing a line of juncture between the microscope slideand the surface of the fluid within the fluidic channel to recede in adirection opposite to that of flow within the fluid section. Invariations of the specific workflow, recession of the line of junctureto facilitate mounting can be accomplished by slowing flow of fluid(e.g., by decreasing a volumetric flow rate of fluid) within the fluidicchannel, by providing relative motion between the fluidic channel andthe microscope slide in a manner that enhances mounting of the tissuesection to the microscope slide, by removing a previously-submergeddisplacing body from a fluid volume within the fluidic channel (i.e., tolower the fluid level within the fluid channel), and/or by any othersuitable mechanism. In the specific workflow, the substrate actuationmodule can further be configured to modulate motion of the microscopeslide to be positioned for placement of multiple sections onto the slideor to be fully retracted to create an unobstructed path to carrydiscarded sections to a reservoir for filtration and/or recirculation.The system 100 can, however, facilitate any other suitable workflow ormethod involving any other suitable section and/or imaging substrate.

In variations wherein the system 100 interacts or integrates with asample sectioning module 103, the system 100 can be configured tocooperate with the sample sectioning module 103 in order to separateserially connected sections generated by the sample sectioning module103 for transmission into the fluid channel 110. In one example of asample sectioning module 103 comprising a microtome 104, as shown inFIG. 2, a blade 3 (e.g., microtome blade) of the microtome 104 isretained in position by a blade holder having a stage 22 that collectstissue sections during normal operation. The microtome 104 can have anadjustable blade angle and an adjustable stage angle α, as shown in FIG.2, that coordinates with an angle of the blade. The stage 22 of themicrotome 104 can thus rotate with an axis of rotation about the tip ofthe blade 3, and the system 100 can mate with the stage 22 along aninterface (e.g., linear interface) between the blade 3 and the system100 such that the blade angle can be adjusted without repositioning ofthe system 100. Furthermore, this configuration allows for lateraladjustment of the blade 3 within the microtome, without repositioning ofthe system 100 in relation to the microtome 104. The system 100 canfurther be hermetically sealed against the stage 22 at the fluid channel110 or manifold 160 (e.g., using a sealing gasket, using mechanicalpressure, etc.) in order to minimize fluid leakage at an interfacebetween the stage 22 and the fluidic channel 110. In one alternative tothe specific example, the system 100 can directly interface with thestage 22 or another portion of the blade-holding portions of themicrotome 104. In another alternative to the specific example, thesystem 100 can include portions that substitute for the stage 22 andcouple directly to blade-holding portions of the microtome 104. Thesample sectioning module 103 can, however, include any other suitableelements or be configured relative to the system 100 in any othersuitable manner.

In the example above, each cut motion of the microtome 104 produces anew section 101, and the embedding material used for the section 101preferably has a density lower than that of fluid (e.g., water) flowingthrough the system 100, such that the section 100 floats on the surfaceof the fluid. Preferably, each generated section 101 remains coupled tothe blade 3 (e.g., loosely coupled to the blade by way of the embeddingmedium), and fluid introduced through a manifold 160 into the fluidchannel 110 at an angle γ frees a preceding section for transmissionthrough the fluid channel 110 and mounting. Flow at the angle γ freesthe preceding section by providing a force that produces tension at ajunction between serial sections generated at the microtome 104.Additionally, in a related example, a portion of fluid flow from themanifold 160 is directed to flow against the stage 22 and in a superiordirection towards the blade 3, which facilitates uniform pulling ofsections away from the blade 3 as they are cut by the blade 3.Furthermore, in the related example, features (i.e., fins) oriented witha direction of fluid flow within the fluid channel 110 at the fluidchannel inlet 120 promote laminar flow away from the blade 3.

Additionally or alternatively, separation of a section 101 from theblade 3 can be performed by generating fluid flow beneath a section 101within the fluid channel 110, such that a shear force induced at ajunction between sections provides separation. Still alternatively, anoperator can manually separate a section 101 from the blade 3 (e.g.,using forceps). Still alternatively, an elevated floor of the fluidchannel inlet 120, immediately downstream of the manifold 160, can causefluid to be drawn away from the blade 3 as it is delivered into thefluid channel 100. Such a configuration, as shown in FIGS. 3A and 3B,enables a cushion of water to develop near the blade 3 with high flowrates, and can allow multiple sections to be separated using flow speedmodulations that retain a section attached to the blade 3, while biasinga preceding section away from the blade 3. Still alternatively, as shownin FIG. 3C, a concave surface 111 of the fluid channel inlet 120 canprovide a “bowl” of fluid that facilitates retention of a sectionattached to the microtome blade 3, while openings of the manifold 160project fluid underneath the section to facilitate separation ofadjoining sections. Multiple orifice angles, as shown in FIG. 3C, canprovide a force that facilitates flexing of adjoining sections, therebypromoting separation from a shear force induced at a junction betweenadjoining sections.

Still alternatively, a separation device of the system 100 (e.g., apaddle, a chuck, a solenoid plunger, etc.) can use mechanical force toseparate adjoined sections. In one example, as shown in FIG. 4A, fluidflow can modulate motion of a separation device 72 a in separatingadjoined sections and allowing a released section to be transmitted intodownstream portions of the fluidic channel 110. In another example witha paddle 72 b, as shown in FIG. 4B, as the microtome chuck rises, a band71 connecting a lever arm on the paddle 72 b to the chuck can pass abovethe paddle's pivot point, causing the paddle to transition to an activeconfiguration. Then, the paddle 72 b can be configured to revert to aninactive configuration, as shown in FIG. 4C, when the chuck descends assections are being sliced from the bulk embedded sample. In yet anotherexample, a solenoid plunger configured proximal the fluid channel inlet120 can provide a force that separates a section from an adjoiningsection.

Once a section 101 has been separated in any of the above variations andexamples, a shallower depth 25 within the fluid channel 110, asdescribed in further detail below, can allow the section 101 toaccelerate toward downstream portions of the fluid channel 110. In anyof the above examples, having a section 101 adhere to the blade 3 for abrief period of time prior to separation by fluid transmission allows anoperator to observe its quality and intervene in the sample processingprocess, if necessary. Floating a section 101 atop fluid in the fluidchannel 110, with coupling of the section 101 to the blade 3 can furtherfunction to reduce the presence of any wrinkling in the section 101.Additionally or alternatively, in any of the examples,

1.1 System—Fluid Channel

The fluid channel 110 has a fluid channel inlet 120 that receives thesection 101, processed from a bulk embedded sample by a samplesectioning module 103 positioned proximal the fluid channel inlet 120, asection-mounting region 130 downstream of the fluid channel inlet, and afluid channel outlet 140 downstream of the section-mounting region. Thefluid channel 110 functions to receive the section 101 from a samplesectioning module 103, and to deliver the section over a layer offlowing fluid that drives the section for mounting at a downstreamposition. The fluid channel 110 preferably defines a primarily straightflow path; however, in some variations, the fluid channel 110 canalternatively define a curved flow path or any other suitable flow path.Preferably, the fluid channel 110 is wider than a maximum width of thesection in order to facilitate smooth transmission of the section intothe fluid channel 110 (e.g., to prevent jamming) during delivery alongthe fluid channel 110. However, the fluid channel can alternatively haveany other suitable width relative to a width of the section.Furthermore, the width and/or depth of the fluid channel 110 can beconstant or variable, in order to produce desired flow behavior throughportions of the fluid channel 110. As such, constricted portions of thefluid channel 110 can produce higher velocities of fluid flow than lessconstricted portions of the fluid channel 110, given a volumetric flowrate of fluid through the fluid channel 110. In some variations, thefluid channel 110 can have at least one declined portion relative to ahorizontal plane in order to passively facilitate fluid flow. In somevariations, the fluid channel 110 can additionally or alternativelycomprise portions that are flat or inclined relative to a horizontalplane.

The fluid channel inlet 120 is preferably configured proximal to anoutput region of the sample sectioning module 103, in order tofacilitate initial positioning of the section, from the samplesectioning module 103, within the fluid channel inlet 120. In specificexamples, as shown in FIGS. 2 and 5, the fluid channel inlet 120 isconfigured proximal to a blade 3 (e.g., a stationary blade) of amicrotome, wherein interaction between a bulk embedded sample (i.e., abiological sample embedded in wax) and the blade generates the sectionand delivers the section toward the fluid channel inlet 120. In thespecific example, the bulk embedded sample is configured to couple to anactuator that moves the bulk embedded sample relative to the stationaryblade to generate sections; however, variations of the specific examplecan involve any other suitable relative motion between a bulk embeddedsample and a cutting instrument to generate sections. As such, thesystem 100 can be configured to couple directly to or to be positionedadjacent to an output region of a sample sectioning module 103; however,the system 100 can additionally or alternatively be configured such thata user or other entity can transfer a section generated from anysuitable sectioning device to the fluid channel inlet 120 forhistological mounting.

The fluid channel inlet 120 preferably has a width substantially largerthan that of a section 101 generated from a bulk embedded sample, inorder to prevent wrinkling or any other form of damage to the section101 upon transmission into the fluid channel inlet 120. In variations,the fluid channel inlet 120 can have a width that is from 115% to 300%of the width of a section 101 generated by the sample sectioning module103. However, the width of the fluid channel inlet 120 can alternativelybe any other suitable size in relation to a width of a sample generatedat the sample sectioning module 103. Furthermore, the width of the fluidchannel 110 can be modulated from the fluid channel inlet 120, to thesection-mounting region 130, to the fluid channel outlet 140, in orderto facilitate focusing and/or accurate positioning of a section 101 ontoa substrate 102 at the section-mounting region 130; however, the widthof the fluid channel 110 can alternatively be substantially constantacross two or more of the fluid channel inlet 120, the section-mountingregion 130, and the fluid channel outlet 140.

In some variations, the fluid channel inlet 120 can comprise a junction125 at an upstream portion of the fluid channel inlet 120, as shown inFIG. 6A, such that the junction 125 diverts a direction of fluid flowinto the fluid channel 100. As such, the junction 125 can function toprovide a more compact and non-interfering interface between the fluidchannel 110 and the sample sectioning module 103. In one example, thejunction is a 90° junction that allows a section transmitted into thefluid channel 110 to be diverted by an angle of approximately 90°between the sample sectioning module 103 and the fluid channel inlet120. Such a configuration facilitates positioning of the system 100 tointerface with the sample sectioning module 103 in a first configuration(e.g., a coupled configuration), and facilitates removal of the system100 from interfacing with the sample sectioning module 103 in a secondconfiguration (e.g., a decoupled configuration). However, in alternativevariations of the example, an angle of rotation between the fluidchannel inlet 120 and the sample sectioning module 103, provided by thejunction 125 and defined in FIG. 6A as θ, can alternatively range from45° to 315°, or can have any other suitable angle depending uponmorphological parameters of the fluid channel 110 and/or the samplesectioning module 103.

In some variations, the junction 125 can define a region with a raisedfloor 126, in relation to a manifold 160, as described in further detailbelow. The raised floor 126 functions to provide concentration of fluidflow into the fluid channel inlet 120, which allows acceleration of asection 101 floating atop and/or carried by fluid within the region ofthe junction 125 having a raised floor 126. As such, the raised floor126 can provide an inlet reservoir that provides desired initial motioncharacteristics (e.g., velocity, acceleration, flow path, etc.) of asection 101 entering the fluid channel 110. Additionally oralternatively, the junction 125 can define a region that enablesconcentration of fluid flow into the fluid channel inlet 120 by defininga constricted cross-sectional area, perpendicular to a direction offluid flow in the fluid channel inlet 120, in any other suitable manner.For instance, a width and/or depth of a region of the junction 125 canbe decreased within the junction 125, relative to other portions of thefluidic channel 110, thereby concentrating fluid flow into the fluidchannel inlet 120 and accelerating motion of a section 101 within thejunction 125 for a given volumetric flow rate in the junction. Inrelated variations, a curved region of the junction 125 of the fluidchannel inlet 120 (e.g., the raised floor region 126) can include a setof tracks 26, a specific example of which is shown in FIG. 6B, whereinthe set of tracks divide the curved region of the junction 125 into aset of regions with varying fluid heights. The set of tracks 26 thusallow fluid travelling along the outside of the curved region of thejunction 125 (e.g., fluid travelling the greatest distance) to movefaster, thereby fluidically rotating a section 101 as it rounds thecurved region of the junction 125. This preserves an orientation of thesection 101 (e.g., in relation to an orientation from the bulk embeddedsample) and prevents jamming of sections within the system 100.

In some variations, an output region of the fluid channel inlet 120(e.g., defined at an output region of the junction 125) can include alip 127 (e.g., an elevated lip) protruding from a base surface of thefluid channel inlet 120/junction 125, that directs fluid, with a section101, into portions of the fluid channel 110 downstream of the fluidchannel inlet 120. The lip 127 can thus provide desired initial motioncharacteristics (e.g., velocity, acceleration, flow path, etc.) of asection 101 entering portions of fluid channel 110 downstream of the lip127, such that sections travelling within the fluid channel 110 travelin a predictable and/or repeatable manner. The fluid channel inlet 120and/or junction 125 can, however, include any other suitable featuresthat provide predictable flow behavior (e.g., substantially constantstreamlines) that drives motion of sections within the fluid channel110.

The section-mounting region 130 of the fluid channel 110 is preferably aregion of the fluid channel 110 configured between the fluid channelinlet 120 and the fluid channel outlet 140, such that a section 101transmitted into the fluid channel 110 by way of the sample sectioningmodule 103 is configured to be mounted to a substrate 102 at a region ofthe fluid channel 110 downstream of the fluid channel inlet 120 andupstream of the fluid channel outlet 140. Preferably, thesection-mounting region 130 has a depth that can accommodate passage ofan imaging substrate under a section (e.g., by way of the substrateactuation module 190) within the section-mounting region 130, withoutdisturbance (e.g., wrinkling, damage) of the section. In an example, asshown in FIG. 8, the section-mounting region 130 comprises asection-mounting reservoir 132 that is substantially deeper than thedepth of the fluid channel inlet 120 and that allows a substrate to besubmerged to a sufficient depth below a section 101 that has beendelivered into the section-mounting region 130. However, thesection-mounting region 130 can alternatively be configured in any othersuitable manner.

Preferably, the section-mounting region 130 is fluidly coupled to thefluid channel inlet 120 by a chute 135, as shown in FIG. 6A, thatfunctions to transport sections from the fluid channel inlet 120 to thesection-mounting region 130 in a predictable and repeatable manner. Thechute 135 also functions to provide desired motion characteristics(e.g., velocity, acceleration, flow path, etc.) of a section 101 upondelivery into the section-mounting region 130, such that sequentialsections travelling to the section-mounting region 130 reach thesection-mounting region 130 in a consistent and desired manner. In onevariation, the chute 135 can be oriented with a constant slope, definedin FIG. 6A as β, that provides downhill flow for acceleration of asection 101 from the fluid channel inlet 120 to the section-mountingregion 130, as facilitated passively by gravitational force.Furthermore, in variations, the chute 135 can have an adjustable angle,such that the value of β can be adjusted (e.g., using an actuatorcoupled to the chute 135 or another portion of the fluidic channel 110).In specific examples, β has a value from 5-15°, and in variations of thespecific examples, β can have a value from 0-60° to provide desired flowcharacteristics within the chute 135.

Alternatively, the chute 135 can have a varying slope along the lengthof the chute 135, from an upstream portion to a downstream portion ofthe chute 135, such that a profile of the chute 135 in an elevation viewhas a non-linear (e.g., curved) morphology. In one example, an upstreamportion of the chute 135 has a steep slope (e.g., greater than 60°)relative to a horizontal plane, and the slope of the chute transitionsto a substantially flat slope (e.g., less than 2°) in coupling to thesection-mounting region 130.

The chute 135 preferably facilitates focusing and accurate positioningof a section 101 at the section-mounting region, by having a widthdimension that is reduced (e.g., gradually reduced) from the fluidchannel inlet 120 to the section-mounting region 130. In variations, thewidth of a downstream portion of the chute 135, proximal thesection-mounting region 130, has a dimension that is from 105% to 125%of the width of a section 101 generated by the sample sectioning module103, such that the width of the downstream portion of the chute issubstantially reduced relative to the width of the fluid channel inlet120. However, the width of the chute 135 can alternatively be any othersuitable size in relation to a width of a sample generated at the samplesectioning module 103. Additionally or alternatively, accuratepositioning of a section traveling along the chute 135 can befacilitated by generating one or more well-defined streamlines of fluidflow, using channel morphologies that provide hydrodynamic focusing. Inone example, the chute 135 can define a curved path that enableshydrodynamic focusing of a section 101 to a well-defined position at thesection-mounting region 130. In the example, the curved path can have aset of undulations that focus the section 101 from a not-well-definedposition to a well-defined position in a consistent manner.Alternatively, a sonic steering module positioned at any portion of thefluid channel 110 can facilitate accurate positioning of a section.Still alternatively, accurate positioning of a section 101 at thesection-mounting region 130 can be facilitated, by way of the chute 135,in any other suitable manner.

In some variations, the section-mounting region 130 can include a basesurface having a geometric feature 131, as shown such that the geometricfeature 131 is submerged below a fluid line of fluid within the fluidchannel 110, and provides flow characteristics that facilitate mountingof a section 101 to a substrate 102 at the section-mounting region 130.In one such variation, the geometric feature 131 comprises a contouredsurface 133 configured to align a section 101 passing over the geometricfeature 131, by way of fluid flow into the section-mounting region 130,toward a desired position. In aligning the section 101, the contouredsurface produces a force vector that biases the section 101 against asubstrate 102 within the section-mounting region 130 and aligns thesection 101 such that its sides are substantially parallel with longedges of the substrate 102. Alternatively, the section-mounting region130 may omit a geometric feature 131 at a base surface, while stillenabling mounting of a section 101 to a substrate 102 at thesection-mounting region.

The fluid channel outlet 140 is preferably configured downstream of thesection-mounting region 130, in order to provide an outlet for flow fromthe fluid channel 110. The fluid channel outlet 140 is preferably alsoconfigured to facilitate retrieval and/or filtration of undesiredsections from the fluid channel 110. As such, in some variations, thefluid channel outlet 140 can be configured to couple to a filtration andrecirculation module that allows fluid and undesired sections from thefluid channel 110 to be filtered of the undesired elements, whileallowing recirculation of fluid throughout the system (e.g., by way ofthe reservoir 150). However, the fluid channel outlet 140 canalternatively be configured in any other suitable manner.

In one variation, an example of which is shown in FIGS. 6 and 8, thefluid channel outlet 140 comprises a curved spout 142 that allows fluidpassing through the section-mounting region 130 to pass into a reservoir150 that recirculates fluid back into the fluid channel 110.Alternatively, the fluid channel outlet 140 can have any other suitablemorphology that allows fluid from the section-mounting region 130 topass through the fluid channel outlet 140 and into the reservoir 150 forrecirculation. For instance, the fluid channel outlet 140 can includeone or more of: a non-curved spout, a funnel-shaped feature, a manifold,and any other suitable fluid guiding feature that allows fluid to beefficiently delivered into the reservoir 150 (e.g., without leakage,without loss). The fluid channel outlet 140 is preferably configured toreceive fluid passing through the section-mounting region 130 and todeliver fluid into the reservoir 150 whether or not a substrate 102 ispresent within the section-mounting region 120; however, the fluidchannel outlet 140 can alternatively be substantially obstructed when asubstrate 102 is present within the section-mounting region 130. Thefluid channel outlet 140 is preferably elevated relative to thereservoir 150, such that fluid from the fluid channel outlet 140 ispassively delivered into the reservoir 150 as facilitated by gravity;however, the fluid channel outlet 140 can alternatively be configuredrelative to the reservoir in any other suitable orientation, wherein adriving element (e.g., pump) facilitates fluid flow from the fluidchannel outlet 140 and into the reservoir 150.

In a specific example of the fluid channel 110′, as shown in FIGS. 6Band 7, the fluid channel inlet 120′ includes a junction 125′ having aregion with a raised floor 126′, in relation to a manifold 160, thatenables acceleration of a section 101 floating atop and/or carried byfluid within the fluid channel inlet 120′. In the specific example, acurved region of the junction 125, at the raised floor region 126,includes a set of tracks 26, wherein the set of tracks divide the curvedregion of the junction 125 into a set of regions with varying fluidheights, as shown in FIG. 6B. The set of tracks 26 in the specificexample allow fluid travelling along the outside of the curved region ofthe junction 125 (e.g., fluid travelling the greatest distance) to movefaster, thereby fluidically rotating a section 101 as it rounds thecurved region of the junction 125. In the specific example, the fluidchannel inlet 120′ also includes an elevated lip 127′ protruding from abase surface of the fluid channel inlet 125′, that directs fluid, with asection 101, into portions of the fluid channel 110 downstream of thefluid channel inlet 120. In the specific example, the fluid channel 110is substantially straight between the output region of the fluid channelinlet 120′ and the fluid channel outlet 140, but rotated by 90° at thejunction 125′, in order to provide a more compact and non-interferinginterface with the sample sectioning module 103.

In the specific example of the fluid channel 110′, the fluid channel 110includes a chute 135′ fluidly coupled between the fluid channel inlet120′ and the section-mounting region 130′, wherein the chute 135′ isconfigured to slope in a declined manner from the elevated lip 127′ ofthe fluid channel inlet 120; toward the section-mounting region 130′. Assuch, the chute 135′ provides downhill flow for acceleration of thesection with fluid in the fluid channel 110′. The slope of the declinedportion is defined in FIG. 2 as β and is defined as being from 5-15° inthe specific example, and the section-mounting region 130′ issubstantially flat relative to a horizontal plane, such that the slope βof the fluid channel 110 transitions from being declined upstream of thesection-mounting region 130′ to being flat, relative to a horizontalplane, at the section-mounting region 130′.

In the specific example of the fluid channel 110, the channel width isinitially substantially wider than (e.g., 115-300%) the width of asection 101 generated at the sample sectioning module 103, but thiswidth is then reduced, proximal to the section-mounting region 130′, toa width that is marginally wider (e.g., 105-125%) than the width of thesection 101 by sidewall contours of the fluid channel, in order toenable more accurate positioning of the section within thesection-mounting region 130. In the specific example of the fluidchannel, the section-mounting region 130 comprises a receiving areaincluding a contoured surface 133 at a base surface of the receivingarea that is configured provide a biasing force that aligns the sectiontoward a desired position at a substrate 102 within the section-mountingregion 130. Variations of the specific example of the fluid channel 110can, however, be configured in any other suitable manner and compriseany other suitable fluidic elements that enable accurate and repeatablepositioning of sections at one or more substrates within thesection-mounting region 130. Adjustable sidewall profiles, for instance,and as shown in FIG. 10, can be used to alter an amount of flowrestriction about a substrate 102 to control fluid level heights,control fluid level modulation rates, accommodate samples of varyingsize, and/or adjust lateral positioning of a section 101 at a substrate102.

1.2 System—Reservoir, Manifold, and Filter

As noted above, the reservoir 150 is in fluid communication with thefluid channel outlet 140, and functions to provide a bath of fluid thatcan be delivered into the fluid channel 110 by way of the fluid channelinlet 120. The reservoir is preferably configured to receive fluid(e.g., filtered fluid) from the fluid channel outlet 140 forrecirculation into the system, in order to enable reuse of asubstantially fixed volume of fluid flowing throughout the system 100.As such, the system 100 preferably includes a single reservoir thatallows for fluid recirculation, wherein the single reservoir can berefilled, if needed (e.g., due to fluid loss in evaporation, etc.).However, variations of the system 100 can alternatively include anysuitable number of reservoirs (e.g., a reservoir for fluid delivery intothe fluid channel inlet 120 and a waste reservoir configured to receivewaste fluid from the fluid channel outlet 140) that enable fluid flowinto the fluid channel inlet 120 and fluid flow out of the fluid channeloutlet 140.

The reservoir 150 preferably contains a volume of fluid that has desiredproperties in facilitating transmission of a section 101 along the fluidchannel 110, and mounting of the section 101 onto a substrate 102 at thesection-mounting region 130. In variations, the fluid can becharacterized as one or more of: low-viscosity (e.g., less than 1×10⁻³Pa*s), volatile at temperatures for histological section processing(e.g., volatile at room temperature, volatile within a sample dryingenvironment), non-interacting with histological process reagents (e.g.,histological stains, etc.) to prevent generation of specimen artifacts,non-damaging to a biological specimen of a sample, neutral pH, andinexpensive. Preferably, the fluid circulating through the system 100,by way of the reservoir 150, comprises water; however, alternativevariations of the fluid can comprise any other suitable fluid forhistological section processing. In some variations, an additive can beintroduced and/or neutralized to modify surface tension of the fluid topromote better transport of a section 101 through the fluidic channel,and/or to promote enhanced interactions with a substrate 102. In onesuch example, a hydrophilic additive can be introduced with fluid fromthe reservoir to promote improved transport of a section 101 through thefluidic channel 110.

The manifold 160 is fluidly coupled to the reservoir 150, and functionsto delivers fluid from the reservoir 150 to the fluid channel inlet 120,thereby transmitting fluid flow that drives delivery of the section fromthe fluid channel inlet 110 toward the section-mounting region 130. Themanifold is configured to provide a flow path between the reservoir 150and the fluid channel inlet 120, thereby enabling separation of asection 101 from an adjoining section produced by the sample sectioningmodule 103, facilitating delivery of the section 101 from the fluidchannel inlet 120, and transmitting the section toward thesection-mounting region 130 of the fluid channel 110. Preferably, fluidfrom the reservoir 150 is pumped through one or more tubes 159 into themanifold 160, as shown in FIG. 6A, wherein the manifold 160 isconfigured to divide the flow into a set of openings 162 into the fluidchannel inlet 120. As such, the manifold 160 is preferably configured togenerate laminar flow at the fluid channel inlet 120; however, themanifold 160 can alternatively be configured to generate any othersuitable type of flow (e.g., turbulent flow) at the fluid channel inlet120.

In one variation, as shown in FIG. 11, the manifold 160 has at least twoinlet tubes 159 into the manifold 160 that provide a uniform (e.g.,symmetric) distribution of flow across the openings 162 of the manifold160 with negligible flow resistance. In this variation, the inlet tubes159 are oriented in an opposing manner at opposite sides 158 of themanifold, wherein the opposite sides 158 are substantially parallel withsidewalls defining a longitudinal axis of fluid flow through the fluidchannel 110. In this variation, the set of openings 162 can be arrangedin one or more of: a linear manner that defines a plane of fluid flowsubstantially parallel to that of a base surface of the fluid channel110; a linear manner that defines a plane of fluid flow substantiallynon-parallel to that of a base surface of the fluid channel 110; anon-linear manner (e.g., curved manner defining a concave surface offluid flow, curved manner defining a convex surface of fluid flow,staggered manner, etc.); and in any other suitable manner. In anothervariation, the manifold 160 can have an elongated opening 163 and/or anorifice pattern with a suitably apodized density, which can function toprovide laminar flow into the fluid channel inlet 120 and distribute itmore evenly across the opening(s) 162, thereby eliminating the need fora second inlet tube 159 into the manifold. In another variation, theopenings of the set of openings can be integrated into a single tube atvarying angles in order to facilitate manipulation (e.g., separation) ofthe tissue sections. In yet another variation, as shown in FIG. 12, themanifold 160 can comprise a cavity 164 inferior to a surface withopenings 162, wherein fluid from the reservoir 150 is delivered into thecavity 164, thereby allowing distribution of the set of openings 162 ofthe manifold across a surface (e.g., a planar surface parallel to a basesurface of the fluid channel 110) in a 2D or 3D configuration, ratherthan in a linear configuration. In yet another variation, the manifold160 can be configured to deliver fluid from the reservoir 150 to one orboth of the sidewalls of the fluid channel 100, to produce flow in adirection non-parallel to a longitudinal axis of the fluid channel 110.However, the manifold 160 can be configured to deliver fluid from thereservoir 150 and into the fluid channel inlet 120 using any othersuitable 1D, 2D, or 3D configuration of openings 162, or in any othersuitable manner.

The manifold 160 is preferably in fluid communication with a pump 167coupled between the reservoir 150 and the manifold, as shown in FIG. 1,wherein modulation of behavior of the pump 167 is governed by acontroller 168. The pump 167 can be configured to provide positivepressure and/or negative pressure in driving fluid between the reservoir150 and the manifold 160. As such, in one mode, forward flow generatedby the pump 167 can facilitate forward movement of a section 101 throughany portion of the fluid channel 110, and in another mode, reverse flowgenerated by the pump 167 can facilitate reverse movement of a section101 through any portion of the fluid channel 110. Furthermore, forwardand/or reverse flow can be adjustable to provide desired flow parameters(e.g., velocities, etc.) for processing of a single section or multiplesections in sequence. Modulation of flow (e.g., with a brief period ofelevated flow rate) can additionally or alternatively be used to providea biasing force that delivers a section 101 toward a substrate 102 formounting.

In one variation, the pump 167 is a positive displacement pump, and inan example of this variation, the pump 167 is a peristaltic pump. Inother examples, the pump 167 can include any one or more of: a gearpump, a screw pump, a piston pump, a progressing cavity pump, aroots-type pump, a plunger pump, a diaphragm pump, a rope pump, animpeller pump, and any other suitable type of pump. Furthermore, thesystem 100 can include more than one pump 167 configured at desiredpositions relative to the fluidic channel 110, the reservoir 150, andthe manifold 160. The pump 167 preferably has a known flow rate to pumpspeed ratio, such that control of the speed of the pump 167 correspondsto a control of the flow rate of the fluid within the fluid channel 110.Furthermore, the pump 167 is preferably configured within the system 100such that the system 100 is relatively easy to assemble, light to haul,quick to control, and easy to clean.

The controller 168 is preferably configured to respond to inputsprovided by an operator of the system 100, in modulating flow parametersof fluid within the system 100. In one variation, the controller 168 canbe configured to access a lookup table that facilitates correlation ofan input from an operator of the system 100 to a desired flow parameter(e.g., flow rate) of the fluid within the fluid channel 110. The lookuptable preferably includes data based on one or more of: historicalbehavior of the system 100, historical runs of other units of the system100, empirical data conducted and developed by the manufacturer ordeveloper of the system 100, and any other suitable data. The storedinformation preferably includes the type of fluid circulating throughoutthe system, characteristics (e.g., dimensions, embedding medium, etc.)of sections generated by a sample-sectioning module 103 in communicationwith the system 100, number of sections being processed by the system100 at a given time, potential errors in performance by the system 100,and any other suitable information. The controller 30 can also befurther adapted to access the lookup table via a computer processingnetwork.

In another variation, the controller 168 can include a storage devicewith accessible memory. A user interface at which an operator providesinputs for control of the system 100, along with the accessible memoryof the storage device, can thus permit the operator to access storedinformation about runs of the system 100 and the system configurationand settings that were utilized during those runs. The storedinformation can include one or more of: the type of fluid circulatingthroughout the system, characteristics (e.g., dimensions, embeddingmedium, etc.) of sections generated by a sample-sectioning module 103 incommunication with the system 100, number of sections being processed bythe system 100 at a given time, a history of errors in performance bythe system 100, and any other suitable information. This storedinformation can be accessed by the operator and retrieved by thecontroller 168 and/or systems. The operator can then, by interfacingwith the controller 168, automatically set up the flow parameters forthe system 100, by utilizing those previous sample run settings.Furthermore, once a run of the system 100 has been completed, anoperator can save the controller settings and use the saved informationfor future runs for processing similar sections or specimens.

Flow modulation within the system 100 can, however, be additionally oralternatively enabled by using one or more valves that adjust flow(e.g., redirect flow, stop flow, open flow, etc.) to differentreservoirs (e.g., a buffer reservoir) within or relative to the fluidchannel 100. Additionally or alternatively, a gate can be used totemporarily block passage of flow upstream of the section-mountingregion 130, thereby creating a desired drop in fluid level at thesection-mounting region 130, independent of a speed of operation of thepump 167. The gate can also function to prevent a section from driftingback in an upstream direction. In operation, if pump speed remainsunaltered, a fluid level on an upstream side of the gate willtemporarily rise until the gate is removed from an obstructing position.Automation of action of the valve(s) and/or gate(s) can be facilitatedby the controller 168 described above, or any other suitable element.

As noted above, in some embodiments, the system 100 can additionally oralternatively include a filter 170, fluidly configured between the fluidchannel outlet 140 and the manifold 160, as shown in FIG. 1, thatfunctions to prevent undesired substances from flowing into the fluidchannel inlet 120. The filter 170 preferably has a physical membranethat prevents substances having a governing dimension above a thresholdsize (e.g., defined by pores in the membrane); however, any othersuitable mechanism can facilitate filtration of undesired substancesfrom the fluid channel 110. In one variation, the filter 170 can beconfigured immediately downstream of the fluid channel outlet 140, inorder to prevent undesired substances from entering the reservoir 150.Additionally or alternatively, the system 100 can include a filter 170configured within the reservoir, but upstream of the pump 167, in orderto prevent undesired substances from affecting proper function of thepump 167 and/or reaching the manifold 160 during recirculation of fluidinto the fluid channel 110. Additionally or alternatively, the filter170 can be configured at any other suitable portion of a fluid loopdefined across the manifold 160, the fluid channel 110, and thereservoir 150. The filter 170 is preferably configured to be areplaceable element of the system 110 in order to promote ease ofmaintenance; however, the filter 170 can alternatively be configured inany other suitable manner. Variations of the system 100 can include asingle filter, or can alternatively include multiple filters configuredto provide redundancy in removing undesired substances from the fluidloop of the system 100.

1.3 System—Substrate Actuation Module

The system 100 can additionally or alternatively include a substrateactuation module 190 that transmits the substrate into thesection-mounting region in a first operation, and delivers the substratefrom the section-mounting region, with the section mounted to thesubstrate, in a second operation. The substrate actuation module 190 isconfigured to couple to an imaging substrate 102, and functions to movethe substrate relative to the section-mounting region 130 of the fluidchannel 110 to facilitate placement of a section 101 onto the substrate102 in an accurate and repeatable manner.

As shown in FIG. 6A, the substrate actuation module 190 can comprise agripper 191 configured to couple to at least one surface 106 of asubstrate 102 (e.g., glass slide), without obstructing mounting of asection 101 to the substrate, by any one or more of: friction, adhesion,compressive force, and any other suitable mechanism, in a manner that isconsistent across all imaging substrates utilized by the system 100.Furthermore, the substrate actuation module 190 preferably comprises anactuator 192 configured to induce motion of the gripper 191 and/or theimaging substrate along a path relative to a section at thesection-mounting region 130 of the fluid channel. In one variation, theactuator 192 is a linear actuator configured to transmit the imagingsubstrate along a linear and sloping path into a reservoir of fluiddefined at the section-mounting region 130 (e.g., immediately downstreamof a section at the section-mounting region 130), as described above;however, the actuator 192 can alternatively be configured to transmitthe substrate 102 along any other suitable path that facilitatesmounting of the section 101 onto the substrate 102. The path along withthe actuator 192 transmits the substrate 102 can be constrained by arail 193, as shown in FIG. 6A or can alternatively be constrained orunconstrained in any other suitable manner.

Preferably, actuation in the substrate actuation module 190 isconfigured to coordinate with flow, from the fluid channel inlet 120, tothe section-mounting region 130 and out of the fluid channel outlet 140.As such, the substrate actuation module 190 is preferably configured tocooperate with or be co-governed by the controller 168 of the pump 167,in synchronizing flow of fluid through the system 100 and mounting ofsections 101 to substrates 102 by way of the substrate actuation module190. In some variations, a flow rate into the fluid channel 110 can bereduced or halted by the controller 168 of the pump 167 to stabilize aposition of the section 101 at the section-mounting region 130 prior tomounting; however, flow can be adjusted in any other suitable manner andwith any suitable sequence that facilitates mounting of the section 101to a substrate 102.

In an example operation of the substrate actuation module 190, as shownin FIGS. 13A-13C, the substrate actuation module 190 coordinates withflow into the fluid channel 110 as governed by the controller 168 of thepump 167. In a first phase of the example operation, as shown in FIG.13A, a section 101 b has been transported to the section-mounting region130, as driven by fluid flow into the fluid channel 110 by the pump 167.In the first phase of the example operation, flow is provided into thefluid channel 110 to bring the section 101 toward the section-mountingregion 130, with a substrate 102 partially submerged within thesection-mounting region 130 by the substrate actuation module 190. Inthe phase portion of the example operation, as shown in FIG. 13A, asection 101 a has already been mounted to the substrate 102, and anadditional section 101 b is in position, at the section-mounting region130, to be mounted to the substrate 102. In the state shown in FIG. 13Awith regions of the substrate 102 and section 101 defined in FIG. 14,the fluid level 27 in the fluid channel 110 is lower downstream of thesubstrate 102 than it is upstream of the substrate 102, and the basesurface 15 and sidewall 14 geometries of the fluid channel 110 at thesection-mounting region 130 are configured to constrain the section 101b to a desired lateral substrate position 31. The sidewalls 14 of thefluid channel 110, as shown in FIG. 6A, then widen around the substrate102 at the section-mounting region 130 to provide a surface watervelocity sufficient to maintain a position of the section 102 b intendedto be mounted, even during flow speed reduction induced by thecontroller 168. In the example operation, the sidewalls 14 aresufficiently close to the substrate 105 sides to provide enoughconstruction, such that a drop in the fluid level 27 across thesubstrate 102 occurs during mounting of the section 101 b to thesubstrate 102. In the first phase of the example operation, shown inFIGS. 13A and 14, the depth that the substrate 102 is submerged in thesection-mounting region 130 establishes a line of juncture 30 betweenfluid in the section-mounting region 130 and the top of the substrate102, and therefore a vertical position 29 of the section 101 b beingmounted to the substrate 102.

In a second phase of the example operation, as shown in FIG. 13B,reducing the flow rate of fluid in the fluid channel 110 causes thesection 101 b to be secured to the substrate 102. An edge 108 of thesection 101 b that is in contact with the substrate 102 is the firstportion of the section 101 b to be mounted to the slide, and as thefluid level equilibrates within the section-mounting region 130, more ofthe section 101 b is mounted to the substrate 102. In the second portionof the example operation, the entire section 101 b is mounted onto thesubstrate 102 prior to mechanical retraction of the substrate from thesection-mounting region 130 by the substrate actuation module 190;however, variations of the example operation can include any othersuitable workflow that does not involve mounting of an entire section101 b prior to retraction of the substrate 102 from the section-mountingregion 130. For instance, only a portion of the section 101 b can belaid onto a substrate 102 by flow modulation in the fluid channel 110,and mechanical retraction of the substrate 102 from the section-mountingregion 130 by the substrate actuation module 190 consummates mounting ofthe section 101 b to the substrate by way of substrate withdrawal and anadhesion force produced by fluid between the section 101 b and thesubstrate 102. Alternatively, mechanical retraction of the substrate 102from the section-mounting region 130 can cause application of thesection 101 b to the substrate 102 substantially without modulation of aflow rate within the fluid channel 110 by the controller 168 of the pump167. Additionally or alternatively, modulation (e.g., lessening) of anangle of a substrate 102 within the section-mounting region 130, by thesubstrate actuation module 190, can be used to apply a section 101 bonto a substrate.

In a third portion of the example operation, as shown in FIG. 13C,retraction of the substrate 102 from the section-mounting region 130provides a flow path (e.g., an unobstructed path) that allows undesiredsubstances 28 (e.g., debris and discarded sections) to be removed byflowing out of the fluid channel outlet 140, and optionally, through afilter 170.

1.4 System—Temperature Regulation and Wrinkle Removal Module

As shown in FIG. 1, the system 100 can additionally or alternativelyinclude a temperature regulating module 180 in contact with fluid fromthe reservoir, that adjusts a temperature of fluid within the fluidchannel. As such, in facilitating mounting of sections at substrates,fluid from the reservoir 150 or portions of the fluid channel 110 can betransmitted at a desired temperature throughout the system. The desiredtemperature is preferably contained within a range of temperatureshaving a higher limiting temperature and a lower limiting temperature.The higher limiting temperature is preferably configured such that anembedding medium (e.g., paraffin wax) surrounding a specimen of asection 101 does not completely melt, and the lower limiting temperatureis preferably configured such that the section 101 does not contract ina manner that could cause wrinkling or other damage of the section 101.

In one variation, the temperature-regulating module 180 can be incommunication with reservoir 150 in a manner that provides regulation ofthe temperature of fluid within the reservoir 150, as it is transmittedfrom the reservoir 150 into the fluid channel inlet 120. As such,temperature of the fluid at the reservoir 150 can be adjusted prior todelivery into the fluid channel 110. Additionally or alternatively, thetemperature-regulating module 180 can be in communication with anyarbitrary position in the flow path of the fluid channel 110 to create alocalized temperature profile at a desired portion of the fluid channel110, without requiring regulation of the entire volume of fluid in thereservoir 150. In yet another alternative variation, thetemperature-regulating element may induce indirect (e.g., non-contact)temperature variation of a section 101 at any point along flow throughthe fluid channel 4 (e.g., by air convection or radiant/infraredheating) without requiring direct thermal conduction between fluid inthe fluid channel 110 or fluid at the reservoir 150, and atemperature-regulating module 180. The reservoir 150 and/or the fluidchannel 110 can, however, be configured in any other suitable manner.

The system 100 can additionally or alternatively include awrinkle-removal module 50, as shown in FIGS. 6 and 15, that functions toreduce or eliminate any wrinkling of sections prior to or duringmounting to a substrate 102. The wrinkle-removal module 50 can beconfigured proximal to the section-mounting region 130 of the fluidchannel 110, and functions to affect a local fluid parameter near asection in the section-mounting region 130, such that the section 101 issubstantially void of wrinkles prior to, during, and/or after couplingof the section 101 to a substrate 102. The wrinkle-removal module 50preferably modulates a local fluid temperature within thesection-mounting region 130, in coordination with delivery of thesection 101 from the fluid channel inlet 120 to the section-mountingregion 130, as facilitated by the controller 168 of the pump 167. Assuch, in a first variation, an example of which is shown in FIG. 16, thewrinkle-removal module 50 can include an injector 51 configured toinject a volume of fluid (e.g., from the reservoir, from another fluidsource) into the fluid channel 110 proximal the section-mounting region130, wherein fluid from the injector 51 is at a temperature configuredto increase fluidity of the section (e.g., a wax section) within thesection-mounting region 130. In this variation, the temperature of thefluid from the injector 51 is preferably elevated relative to a globalfluid temperature within the fluid channel, to provide a local fluidtemperature (e.g., to 40-60° C.) that increases fluidity of the sectionwithout complete dissociation or melting of the section. However, fluidcan alternatively be provided from the injector 51 at any other suitabletemperature that facilitates wrinkle removal in a section. In thisvariation, the system 100 can include a switch (e.g., 3-way switch)configured to switch between a first configuration in which fluid at alower temperature from the reservoir 150 is circulated into the fluidchannel 110 by way of the fluid channel inlet 120, and a secondconfiguration in which fluid at an elevated temperature (e.g., as passedthrough a heating apparatus upstream of the injector 51) is circulatedinto the fluid channel 110 by way of the injector 51. Additionally oralternatively, a flow rate used to deliver fluid at an elevatedtemperature from the injector 51 can be higher, lower, or substantiallyequal to a flow rate used to deliver fluid at a lower temperature intothe fluid channel inlet 120.

In a first example of the first variation, the injector 51′ can bepositioned superior to and upstream of the section-mounting region 130,as shown in FIG. 17A, in order to inject high-temperature fluid into thefluid channel 110 upstream of the section-mounting region 110, such thatthe high-temperature fluid flows under a section within the sectionmounting region 130 to remove any wrinkles in the section, prior tomounting of the section 101 to a substrate 102. In a second example ofthe first variation, as shown in FIG. 17B, the injector 51″ can bepositioned downstream of the section-mounting region 130 and configuredto inject high-temperature fluid upstream into the section-mountingregion 130, in order to remove any wrinkles in a section within thesection-mounting region 130. In a third example of the first variation,as shown in FIG. 17C, the injector 51′″ can be positioned directlyinferior to a section 101 within the section-mounting region 130 (e.g.,at a base surface of the fluid channel 110, within a reservoir intowhich the imaging substrate is directed for mounting of the section),such that high-temperature fluid is injected in an inferior-to-superiordirection, toward the section 101, to remove any wrinkles. In onevariation of the third example, the fluid channel 110 can include areservoir proximal the section-mounting region 130, at which the sectionis held stationary and exposed to fluid at an elevated temperature, fromthe injector 51, prior to mounting of the section to the imagingsubstrate. In another variation of the third example, a substrate 102can be positioned (e.g., at an angle, perpendicularly) with an edgeagainst the base surface of the fluid channel 110 proximal thesection-mounting region 130 to create a dam, fluid at an elevatedtemperature can be delivered toward the imaging substrate from theinjector 51 and trapped by the dam formed by the imaging substrate, anda section 101 positioned upstream of the dam can thus be positioned overa volume of fluid at an elevated temperature to undergo de-wrinkling.Then, the substrate can be positioned away from the base surface of thefluid channel 4, thereby breaking the dam and allowing the section to bemounted to the imaging substrate, free of wrinkles, as the fluid levelin the fluid channel 110 drops.

In a fourth example of the first variation, the injector 51 can beconfigured to deliver high-temperature fluid from sidewalls of the fluidchannel 110 proximal section-mounting region 130, in order to remove anywrinkles in a section within the section-mounting region. In a fifthexample of the first variation, the injector 51 can be configured todeliver fluid at an elevated temperature through the same manifold 160used to deliver fluid from the reservoir 150 into the fluid channelinlet 150, in order to provide fluid at a suitable temperature forde-wrinkling of a section. In one variation of the fifth example, theentire volume of fluid from the reservoir 150 can be elevated to adesired temperature for de-wrinkling of a section, and delivered throughthe manifold 160, by the injector, such that all fluid flowing withinthe fluid channel 110 is elevated to the desired temperature. In any ofthe above examples of the first variation, the section 101 can be heldstationary by the substrate 102 or any other suitable object as fluidfrom the injector 51 flows under the section. Furthermore, a length oftime over which the section 101 sits atop fluid at an elevatedtemperature can be adjusted according to requirements of a sample-type(e.g., tissue type) of the section, for instance, by adjusting flowrates of fluid into the fluid channel 110 and/or adjusting a position ofthe section by way of the substrate actuation module 190. Variations ofthe injector 51 of the first variation can, however, be configured inany other suitable manner or implement combinations of any of the aboveexamples/variations.

In a second variation of the wrinkle-removal module 50 involving localtemperature adjustment, the wrinkle-removal module 50 can additionallyor alternatively include a heating module 52 configured to provideconvective and/or radiant heat transfer toward a section at thesection-mounting region 130. As shown in FIG. 18, the heating module 52can be configured to transmit heat toward one or more surfaces of thesection 101, from a direction superior to and/or inferior to the section101. Furthermore, the heating module 52 can be configured to deliverheat toward the section prior to, during, and/or after contact betweenthe section and a surface of a substrate 102. As such, the heatingmodule 52 can be configured to transmit heat toward the section 101 bylocally heating fluid within the section-mounting region 130 and/or bytransmitting heat through air toward a surface of the section 101 at thesection-mounting region 130, with or without a substrate 102 present. Ina first example of the second variation, the heating module 52 cancomprise a heating element positioned at a base surface of thesection-mounting region 130 and inferior to a section at thesection-mounting region 130, such that the heating element locally heatsfluid (e.g., by convective heat transfer) at an inferior surface of thesection, thereby facilitating wrinkle removal. In a second example ofthe second variation, the heating module 52 can comprise heatingelements spanning sidewalls of the fluid channel 110 proximal to (e.g.,upstream of, adjacent to, downstream of, etc.) the section-mountingregion 130, such that the heating elements locally heat fluid (e.g., byconvective heat transfer) from lateral directions to facilitate wrinkleremoval. In a third example of the second variation, the heating module52 can comprise a heating element positioned superior to a section atthe section-mounting region 130, configured to provide radiant and/orconvective heat transfer through air toward the section at thesection-mounting region 130. In one variation of the third example,heated air from the heating module 52 can be delivered toward asubstrate 102 with the section 101, in order to heat the section 101 andresidual fluid between the section and the imaging substrate to providea de-wrinkling mechanism. Variations of the heating module 52 of thesecond variation can, however, be configured in any other suitablemanner or implement combinations of any of the aboveexamples/variations. Furthermore, delivery of heat from the heatingmodule 52 to the section can be performed multiple directionssimultaneously, and/or in any other suitable sequence of directions.

In any of the above examples and variations, the injector 51/heatingmodule 52 can be configured cyclically or non-cyclically varytemperatures proximal to a section within the section-mounting region130, in order to induce thermal expansion and contraction of the section101. In these variations, repeated expansion and/or contraction of thesection can allow removal of any wrinkles that would remain after asingle instance of heating of the section. Furthermore, in any of theabove examples and variations, the injector 51/heating module 52 can beconfigured to move (e.g., by coupling to an actuator) relative to asection 101 (e.g., by moving the injector/heating module, by moving animaging substrate or the section relative to the injector/heatingmodule) at the section-mounting region 130, such that heat can beprovided consistently to sections at the section-mounting region 130 ina dynamic manner. Moving and/or adjusting an angle of a substrate 102with the section 101 relative to a heating module 52 can, for instance,facilitate wicking of fluid from the substrate 102 and facilitate dryingof a section 101 during de-wrinkling, as shown in FIG. 19. Heating bythe wrinkle-removal module 50 can furthermore be performed continuouslyas a stream of sections flow into the section-mounting region, orintermittently, for each section that flows in the section-mountingregion.

In alternative variations, the wrinkle-removal module 50 can adjustlocal fluid behavior (e.g., flow behavior, viscosity behavior, etc.)proximal to a section within the section-mounting region 130, in orderto facilitate wrinkle removal within a section for mounting. In onealternative variation, the wrinkle-removal module 50 can generateuniformly or non-uniformly diverting flows proximal to (e.g., directlyinferior to) a section at the section-mounting region 130 that provideforces that expand the section. In examples of this variation, thediverting flows can include two or more flow paths directed outward froma point proximal to a center point of a section 101 at thesection-mounting region 130. In another alternative variation, thewrinkle-removal module 50 can include an injector configured to transmita fluid, different from fluid flowing from the fluid channel inlet 120to the fluid channel outlet 140, that provides an expanding force (e.g.,based upon differences in density, based upon differences in viscosity,etc.) at a surface of a section 101 at the section-mounting region 130.In another alternative variation, as shown in FIG. 20, thewrinkle-removal module 50 can include a vibration module 53 configuredto generate vibration waves proximal to a section at thesection-mounting region 130, in order to facilitate wrinkle removal. Inexamples of this variation, the vibration module 53 can be configured togenerate vibrations mechanically and/or acoustically, and can beconfigured to generate standing and/or non-standing waves. Variations ofthe wrinkle-removal module 50 can, however, comprise any other suitableelements configured to facilitate wrinkle removal by any other suitablemechanism.

In still alternative variations, the wrinkle removal module 50 can beconfigured to transfer heat to the substrate 102, in order to increasethe temperature of the substrate 102 to remove wrinkles in a section 101that contacts the heated substrate 102. As such, the wrinkle removalmodule 50 can comprise a heating element (e.g., heating plate, array ofheating chips, etc.) configured to contact at least one surface of thesubstrate 102 and/or radiate heat toward the substrate 102, as shown inFIG. 21, prior to or during mounting of the section 101 to the substrate102 in order to remove wrinkles in the section 101. In specificexamples, the heating element can be integrated with the substrateactuation module 190 that is configured to manipulate motion of thesubstrate 102, or can be configured to contact the substrate 102 in anyother suitable manner.

Furthermore, the wrinkle-removal module 50 can be configured tocoordinate with flow, from the fluid channel inlet 120, to thesection-mounting region 130, as facilitated by the controller 168 of thepump 167 coupled to the manifold 160. In some variations, a flow rateinto the fluid channel 110 can be reduced or halted to stabilize aposition of the section at the section-mounting region 130, therebyfacilitating wrinkle removal within the section 101. Flow within thefluid channel 110 can, however, be configured in any other suitablemanner in coordination with the wrinkle-removal module 50.

In one example operation, involving coordination between flow governedby the controller 168 of the pump 167, the wrinkle-removal module 50,and the substrate actuation module 190, the substrate actuation module190 can be configured to transmit a substrate 102 to a desired fluiddepth 29, as shown in FIG. 22A, within the section-mounting region 130of the fluid channel 110. Then, a section 101 can be transmitted towardthe section-mounting region 130 from the fluid channel inlet 110 afterseparation from a blade 3 of a microtome 104 of a sample-sectioningmodule 103, as shown in FIG. 22B, and the wrinkle-removal module 50 caninject a volume of high-temperature fluid toward the section 101 toremove wrinkles, as shown in FIG. 22C. Flow from the fluid channel inlet120 can then be increased to facilitate delivery of the section 101 ontothe substrate 102 as the substrate 102 is retracted from thesection-mounting region 130 by the substrate actuation module 190, asshown in FIG. 22D. In variations involving mounting of multiple sectionsonto a single substrate 102, the above example can be repeated multipletimes, with the substrate 102 delivered into the section-mounting region130 of the fluid channel 110 at successively decreasing depths for eachsection 101 mounted to the substrate 102. Variations of the example can,however, involve any other suitable workflow.

1.5 System—Additional Elements and Alternative Configurations

Variations of the system 100 can alternatively omit any of the abovedescribed elements in order to provide simplified variations of thesystem 100. For instance, one variation of the system 100 can include areservoir 150 comprising fluid and configured to receive a section 101at a surface of fluid in the reservoir 150; and a wrinkle removal module50 configured proximal to the section within the reservoir. In thissimplified variation, the wrinkle removal module 50 can facilitateexpansion of the section using one or more mechanisms as describedabove, and a human technician or other entity can mount the expandedsection onto an imaging substrate manually or automatically. Variationsof the above embodiments can further include any other suitable elementsconfigured to facilitate mounting of a section onto an imagingsubstrate. For instance, a variation of the system 100 can include atracking module configured to track a position of a section, and tofacilitate wrinkle-removal within the section at any desired position incoordination with the tracking module. The system 100 can, however, omitand/or incorporate any other suitable element(s), or have alternativeconfigurations, some of which are described below.

In one variation of the system 100, one or more sensors 75 can be placedalong the fluid channel 110 to enable detection of sections 101 as theypass, as shown in FIG. 23. The sensors can operate using any one or moreof: infrared emitter-detector pairs, capacitive sensing, light contrastdetection, image processing, and any other suitable mechanism to detectthe presence, type, shape, and/or condition of a section 101 beingtransmitted through the fluid channel 110. Such sensors can function tofacilitate appropriate timing of flow modulation for placement of asection 101 onto a substrate 102, as governed by a controller 168 of apump 167 of the system 100. Such sensors can additionally oralternatively enable detection of the presence or absence of fluid inthe fluid channel 110, a velocity of a section 101 as it is transmittedwithin the fluid channel 110, physical parameters of (e.g., dimensionsof, damage to, etc.) a section 101 within the fluid channel 110, and anyother suitable parameters. Such sensors can additionally oralternatively be used for subsequent, automated and/or manual,decision-making processes to adjust system performance, enable sortingof section, enable labeling or tagging of substrates with relevantinformation, and/or flagging conditions requiring operator intervention.The sensors can be mounted at an underside surface of the fluid channel110 and configured to detect overhead passing sections (e.g., by way oftransparent windows through the base surface of the fluid channel 110),or can additionally or alternatively be mounted above the fluid channel110 and configured to detect sections passing below.

To automate management of substrates for rapid exchange of substrateswith mounted sections and empty substrates, a rail 193 of the substrateactuation module 190 can be mounted on a pivoting element 197, as shownin FIG. 24. As such, the substrate actuation module 190, with a gripper191 mounted to a rail 193 can form a robotic arm that can be used forretrieving and replacing mounted substrates, for submerging substratesat the section-mounting region 130 during section placement, and forretraction to different positions for placement of multiple sections. Tofacilitate automated retrieval and replacement, the substrate actuationmodule 193 can interface with a substrate rack 98 (e.g., rack of imagingslides) having a set of slots (e.g., parallel slots, radially orientedslots, etc.) configured to hold substrates for retrieval andreplacement. Substrate manipulation by the system 100 can, however, beautomated in any other suitable manner.

To facilitate separation of adjoining sections produced by a samplesectioning module 103, the system 100 can include elements that apply atreatment to the top or bottom of an embedded tissue section to createdissimilar materials at a section-section junction, thereby reducing thetendency of sections to wrinkle or form ribbons during processing. Asshown in FIG. 25, the embedding medium 90 can comprise wax, andtreatment 92 can comprise a quick-setting enamel applied to bottoms ofsections 101 to prevent formation of ribbons or wrinkling.

In some variations, the microtome 104 of a sample sectioning module 103interfacing with the system 100 can comprise a temperature-regulatedchuck 33, as shown in FIG. 24, that functions to maintain a bulkembedded sample at a desired temperature for sectioning. Thetemperature-regulated chuck 33 can also allow for consistent productionof high-quality sections even if the bulk embedded sample is left withinthe chuck 33 for extended periods, such as when serial sectioning.

In some variations, the system 100 can include an atomizer 198 or otherelement, as shown in FIG. 24, configured to spray fluid over a sample tohydrate the bulk sample while it is being sectioned by the samplesectioning module 103. The atomizer 198 can thus prevent the need for anoperator to periodically remove, hydrate, and replace a sample duringsectioning of specific types of tissues that are susceptible todehydration and flaking during sectioning. Additionally oralternatively, the system 100 can include a permeable material (e.g.,sponge, fabric, etc.), saturated with a hydrating fluid and configuredto contact the bulk sample (e.g., by providing relative motion betweenthe bulk sample and the permeable material), in order to prevent dryingof the bulk sample. Hydration of the bulk sample to improve sampleprocessing can, however, be performed in any other suitable manner.

In some variations, the system 100 can include a laser-etching devicethat functions to label substrates as they are mounted with sections,thus further reducing a need for operator intervention in substratelabeling. The laser-etching device can further function to reduce apossibility of mismatching substrate-mounted sections with theircorresponding source embedded samples. The laser-etching device can beintegrated with an informational technology (IT) system of a laboratoryor clinic where the system 100 is in use.

In some variations, the system 100 can include an anti-static ionizingdevice that functions to ensure that each section 101 iselectrostatically neutral at certain phases of processing. Theanti-static ionizing device can minimize risk of electrostaticattraction or repelling of a cut section 101 toward a sidewall or otherportion of the fluid channel 110 in a manner that could hinder mountingof the section to a substrate.

In some variations, the system 100 can include a kinetic sensor coupledto a blade 3 and/or sample mounting chuck of the sample sectioningmodule 103 that functions to sense acceleration, vibration, and/or anyother kind of feedback that could be used to automatically adjustcutting motion of the sample sectioning module 103. The kinetic sensorcan thus function to reduce operator interaction and improve automationin the system 100.

In one alternative configuration, sections can be transmitted to asubstrate from a path that is perpendicular to that described in theembodiments and variations above, which allows for a condensed fluidpath. In another alternative configuration, as shown in FIG. 26, alinear flow boost (i.e., a burst of fluid flow) can be used to introduceflow around a submerged substrate 102 at the section-mounting region 130to produce consistent section placement upon a substrate 102.

The system 100 can, however, include any other suitable elementsconfigured to facilitate mounting of one or more sections onto asubstrate. Furthermore, as a person skilled in the art will recognizefrom the previous detailed description and from the figures and claims,modifications and changes can be made to the system 100 withoutdeparting from the scope of the system 100.

2. Method

As shown in FIG. 27, an embodiment of a method 100 for coupling asection to a substrate comprises: providing a fluid channel having afluid channel inlet, a section-mounting region downstream of the fluidchannel inlet, and a fluid channel outlet downstream of thesection-mounting region S210; at the fluid channel inlet, receiving thesection, processed by a sample sectioning module positioned proximal thefluid channel inlet S220; delivering the section from the fluid channelinlet toward the section-mounting region upon transmission of fluid flowinto the fluid channel inlet, wherein transmission of fluid flow intothe fluid channel inlet is governed by a controller S230; at a substrateactuation module, transmitting the substrate into the section-mountingregion to receive the section, in a first operation, in coordinationwith the controller S240; and at the substrate actuation module,delivering the substrate, with the section mounted to the substrate,from the section-mounting region in a second operation, in coordinationwith the controller S250. In some embodiments, the method 200 caninclude any one or more of: transmitting fluid flow through the fluidchannel outlet to be recycled into the fluid channel inlet, by way of areservoir in fluid communication with the fluid channel inlet and outletS260; and at a wrinkle-removal module proximal to the section-mountingregion, transmitting heat toward the section, thereby mitigatingwrinkling of the section at the substrate S270.

The method 200 functions to automate processing of sections (e.g.,histological specimen sections, biological sections, etc.) in a mannerthat consistently generates high-quality mounted sections, with minimalor no effort from a human technician. As such, the method 200 cansignificantly reduce labor-intensive aspects of mounting sections tosubstrates. The method 200 is preferably implemented by at least aportion of the system 100 described in Section 1 above; however, themethod 200 can additionally or alternatively be implemented using anyother suitable system(s).

Block S210 recites: providing a fluid channel having a fluid channelinlet, a section-mounting region downstream of the fluid channel inlet,and a fluid channel outlet downstream of the section-mounting region.Block S210 functions to provide a fluid conveyer that can be used todrive a section for mounting at a substrate. Block S210 is preferablyimplemented using an embodiment of the system 100 described above, andmore specifically, using embodiments, variations, and/or examples of thefluid channel 110, fluid channel inlet 120, section-mounting region 130,and fluid channel outlet 140 described above; however, Block S210 canalternatively be implemented using any other suitable system 100 thatprovides a fluid path, with control of fluid flow parameters forautomatically mounting histological sections to one or more substrates.

Block S220 recites: at the fluid channel inlet, receiving the section,processed by a sample sectioning module positioned proximal the fluidchannel inlet. Block S220 functions to initiate sample reception withinthe fluid channel, such that the sample can be transmitted to downstreamportions for manipulation (e.g., positioning, de-wrinkling) and mountingat a substrate. In Block S220, the section is preferably received from abulk embedded sample processed by a sample sectioning module (e.g.,comprising a microtome with a blade proximal the fluid channel inlet);however, the section can alternatively be received in Block S220 in anyother suitable manner. In some variations, Block S220 can include one ormore of: retaining an edge of the section by way of coupling the edge ofthe section to a cutting instrument of the sample sectioning moduleS222; and releasing the section into the fluid channel inlet uponseparating the section from an adjoining section coupled to the cuttinginstrument of the sample sectioning module S224. Block S224, asdescribed above, can include any one or more of: introducing fluidthrough a manifold into the fluid channel (e.g., at an angle γ) to freea preceding section for transmission into the fluid channel inlet S224a; generating fluid flow beneath a section within the fluid channel S224b, such that a shear force induced at a junction between sectionsprovides separation; manually separating a section from the blade (e.g.,using forceps) S224 c; implementing an elevated floor of the fluidchannel inlet, immediately downstream of the manifold, to cause fluid tobe drawn away from the blade as it is delivered into the fluid channel;using a separation device (e.g., a paddle, a chuck, etc.), as shown inFIGS. 4A-4C, thereby providing a mechanical force that separatesadjoined sections; and using any other suitable method of separatingadjoining sections without damaging sections. Block S220 can, however,include any other suitable steps for transmitting a section that hasbeen cut from a bulk embedded sample into the fluid channel inlet.

Block S230 recites: delivering the section from the fluid channel inlettoward the section-mounting region upon transmission of fluid flow intothe fluid channel inlet, wherein transmission of fluid flow into thefluid channel inlet is governed by a controller. Block S230 functions todrive a section, floating atop fluid within the fluid channel, towardthe section-mounting region of the fluid channel upon transmission offluid through a manifold in fluid communication with the fluid channelinlet. Block S230 is preferably implemented using embodiments,variations, and/or examples of the fluid channel 110, the pump 167, thecontroller 168, and the manifold 160 described in Section 1 above;however, Block S230 can additionally or alternatively be implementedusing any other suitable system or element(s). As shown in FIG. 29,delivering the section toward the section-mounting region in Block S230can thus include any one or more of: providing a progressively narrowfluid path within the fluid channel that enables accurate positioningthe section onto a substrate within the section-mounting region S232;providing a descending fluid path within the fluid channel, therebyusing gravity to facilitate acceleration of the section, atop a layer offluid within the fluid channel, toward the section-mounting region S234;retaining a position of the section at the section-mounting region S236(e.g., upon modulation of fluid flow parameters); and using any othersuitable block that enables accurate placement of a section at asubstrate, in a repeatable manner.

Block S240 recites: at a substrate actuation module, transmitting thesubstrate into the section-mounting region to receive the section, in afirst operation, in coordination with the controller. Block S240functions to position a substrate at a desired depth and/or with adesired angle relative to a base surface of the fluid channel at thesection-mounting region, which allows accurate positioning and mountingof the section to the substrate. Block S240 is preferably implementedusing an embodiment, variation, or example of the substrate actuationmodule 190, substrate 102, and section-mounting region 130 described inSection 1 above; however, Block S240 can alternatively be implementedusing any other suitable system or element(s). In variations, as shownin FIG. 30, Block S240 can include any one or more of: transmitting agripper of the substrate actuation module, with a substrate coupled tothe gripper, along a path defined by a rail, wherein rail defines asloping path into the section-mounting region and constrains motion ofthe substrate along the sloping path S242; defining a line of juncturebetween a portion of the substrate and fluid within the fluid channel atthe section-mounting region S244; receiving the section at the line ofjuncture, thereby initiating mounting of the section to the substrate;modulating a fluid level at the section-mounting region, therebypromoting positioning and/or maintenance of a position of the sectionrelative to the substrate S246; and performing any other suitable actionthat facilitates initial coupling of the section to the substrate. BlockS240 is thus preferably performed in coordination with modulation offlow parameters within the fluid channel by the controller, such thatfluid parameters (e.g., flow velocity, flow acceleration, fluid level,etc.) for promoting accurate and repeatable coupling of a section to thesubstrate is substantially synchronized with motion of the substrateactuation module and coupled substrate.

Block S250 recites: at the substrate actuation module, delivering thesubstrate, with the section mounted to the substrate, from thesection-mounting region in a second operation, in coordination with thecontroller. Block S250 functions to retract a substrate from a positionwithin the section-mounting region, with a section at least partiallycoupled to the substrate, which allows the section to gradually be fullymounted to the substrate. Block S250 is preferably implemented using anembodiment, variation, or example of the substrate actuation module 190,substrate 102, and section-mounting region 130 described in Section 1above; however, Block S250 can alternatively be implemented using anyother suitable system or element(s). In variations, as shown in FIG. 31,Block S250 can include any one or more of: retracting a gripper of thesubstrate actuation module, with a substrate coupled to the gripper,along a path defined by a rail, wherein rail defines a sloping path intothe section-mounting region and constrains motion of the substrate alongthe sloping path S252; modulating a fluid level at the section-mountingregion, thereby promoting mounting of the section onto the substrateS254 by producing an adhesion force between the section and thesubstrate; and performing any other suitable action that facilitatesinitial coupling of the section to the substrate. Block S250 is thuspreferably performed in coordination with modulation of flow parameterswithin the fluid channel by the controller, such that fluid parameters(e.g., flow velocity, flow acceleration, fluid level, etc.) forpromoting mounting of a section to the substrate in an accurate andrepeatable manner is substantially synchronized with motion of thesubstrate actuation module and coupled substrate.

In some variations, Blocks S240 and S250 can be iteratively repeated formounting of multiple sections to a single substrate, wherein a substrateis delivered to progressively decreasing depths within thesection-mounting region to enable reception of multiple sections atdesired positions along the substrate. An example workflow of mountingmultiple sections to a single substrate is shown in FIGS. 13A-13C.

In some variations, the method 200 can include Block S260, whichrecites: transmitting fluid flow through the fluid channel outlet to berecycled into the fluid channel inlet, by way of a reservoir in fluidcommunication with the fluid channel inlet and the fluid channel outlet.Block S260 functions minimize wasting of fluid by the system, by usingrecirculated fluid to process samples. Block S260 is preferablyimplemented using embodiments, variations, and/or examples of the fluidchannel outlet 140, the reservoir 150, the pump 167, the controller 168,the filter 170, and the manifold 160 described in Section 1 above;however, Block S260 can alternatively be implemented using any othersuitable system or elements. Block S260 preferably includes providing aflow path from the fluid channel to the reservoir, by way of the fluidchannel outlet, and can additionally or alternatively include one ormore of: filtering fluid at least at one of the fluid channel outlet,the reservoir, the pump, and the manifold S262, thereby removingundesired substances prior to recirculation of fluid through the system;modulating a temperature of fluid at least at one of the reservoir, themanifold, and a portion of the fluid channel S264; introducing anadditive for surface tension modulation along with fluid from thereservoir, during recirculation S266; and any other suitable step thatfacilitates recycling of fluid in the system with minimal operatorinvolvement.

In some variations, the method 200 can additionally or alternativelyinclude Block S270, which recites: at a wrinkle-removal module proximalto the section-mounting region, transmitting heat toward the section,thereby mitigating wrinkling of the section at the substrate. Block S270functions to produce high-quality mounted sections, substantially freeof wrinkling, upon transmitting heat to sections within the system 100at desired stages of processing. Block S270 is preferably implementedusing an embodiment, variation, or example of the wrinkle-removal module50 described in Section 1 above, whereby transmitting heat toward thesection can include any one or more of: injecting fluid with a desiredtemperature toward a section at the section-mounting region S272 (e.g.,from underneath the section, from above the section, upstream of thesection, downstream of the section, from sidewalls surrounding thesection, etc); convectively transferring heat toward at least onesurface of a section S274; heating a substrate to which a section ismounted or is intended to be mounted S276; and using any other suitablemechanism of heat transfer to de-wrinkle a section.

In one variation, as shown in FIGS. 32 and 22A-22D, Block S270 caninclude receiving the section at a fluid channel inlet of a fluidchannel S310; delivering the section from the fluid channel inlet towarda section-mounting region of the fluid channel by way of fluid flow froma manifold proximal to the fluid channel inlet S320; delivering animaging substrate into fluid at the section-mounting region at a firstdepth S330 by way of a substrate actuation module; elevating a localtemperature of fluid at the section-mounting region in coordination withdelivery of the section into the section-mounting region S340 to producean expanded section; increasing flow into the section-mounting region,thereby delivering the expanded section toward the imaging substrateS350; and withdrawing the imaging substrate from the section-mountingregion by way of the gripper module S360, thereby coupling the sectionto the imaging substrate.

However, Block S270 can alternatively include removing wrinkles from asection prior to, during, or after mounting, using any other suitableapparatus. For instance, Block S270 can include preventing wrinkling ofa section by modulating a viscosity parameter or surface tensionparameter of the fluid conveying the section to the section-mountingregion, or by using acoustic vibrations to remove wrinkles from asection.

The method 200 can, however, include any other suitable blocks or stepsconfigured to facilitate mounting of one or more sections onto asubstrate in an automated or semi-automated manner. In one variation,the method 200 can include detecting, at a sensor system, one or moreof: a section passing through a portion of the fluid channel, presenceor absence of fluid in the fluid channel, a velocity of the section asit is transmitted within the fluid channel, physical parameters of(e.g., dimensions of, damage to, etc.) the section within the fluidchannel 110, and any other suitable parameters. In related variations,the method 100 can include timing flow modulation for placement of thesection onto the substrate in response to signals generated by thesensor system.

In variations, the method 200 can additionally or alternatively includeone or more of: applying a treatment to a portion of a bulk embeddedsample used to generate the section, in order to prevent sectionwrinkling; automatically regulating a temperature of the bulk embeddedsample; automatically spraying fluid over a portion of the bulk embeddedsample to hydrate the sample while it is being sectioned by a samplesectioning module; with a laser-etching device, automatically labelingsubstrates as they are mounted with sections; with an anti-staticionizing device, ensuring that the section is at an electrostaticallyneutral state during processing; based upon signals from a kineticsensor coupled to the sample-sectioning module, automatically modulatingsectioning parameters to improve section quality; and any other suitablestep that automates sample processing and/or improves quality ofsamples.

Variations of the system 100 and method 200 include any combination orpermutation of the described components and processes. Furthermore,various processes of the preferred method can be embodied and/orimplemented at least in part as a machine configured to receive acomputer-readable medium storing computer-readable instructions. Theinstructions are preferably executed by computer-executable componentspreferably integrated with a system and one or more portions of thecontrol module 155 and/or a processor. The computer-readable medium canbe stored on any suitable computer readable media such as RAMs, ROMs,flash memory, EEPROMs, optical devices (CD or DVD), hard drives, floppydrives, or any suitable device. The computer-executable component ispreferably a general or application specific processor, but any suitablededicated hardware device or hardware/firmware combination device canadditionally or alternatively execute the instructions.

The FIGURES illustrate the architecture, functionality and operation ofpossible implementations of systems, methods and computer programproducts according to preferred embodiments, example configurations, andvariations thereof. In this regard, each block in the flowchart or blockdiagrams may represent a module, segment, step, or portion of code,which comprises one or more executable instructions for implementing thespecified logical function(s). It should also be noted that, in somealternative implementations, the functions noted in the block can occurout of the order noted in the FIGURES. For example, two blocks shown insuccession may, in fact, be executed substantially concurrently, or theblocks may sometimes be executed in the reverse order, depending uponthe functionality involved. It will also be noted that each block of theblock diagrams and/or flowchart illustration, and combinations of blocksin the block diagrams and/or flowchart illustration, can be implementedby special purpose hardware-based systems that perform the specifiedfunctions or acts, or combinations of special purpose hardware andcomputer instructions.

As a person skilled in the art will recognize from the previous detaileddescription and from the figures and claims, modifications and changescan be made to the preferred embodiments of the invention withoutdeparting from the scope of this invention as defined in the followingclaims.

We claim:
 1. A system for mounting a section onto a substrate, thesystem comprising: A blade that, during operation, generates the sectionfrom a bulk sample retained within a sample sectioning module; a fluidchannel positioned at an output region of the blade and including: afluid channel inlet that receives the section from the blade, and asection-mounting region downstream of the fluid channel inlet; and afluid channel outlet; a reservoir in fluid communication with the fluidchannel outlet; and a manifold, fluidly coupled to the reservoir, thatdelivers fluid from the reservoir to the fluid channel inlet, therebytransmitting fluid flow that drives delivery of the section from thefluid channel inlet toward the section-mounting region.
 2. The system ofclaim 1, further comprising a filter, fluidly configured between thefluid channel outlet and the manifold, that prevents undesiredsubstances from flowing into the fluid channel inlet.
 3. The system ofclaim 1, wherein the fluid channel inlet includes a junction at anupstream portion of the fluid channel inlet, the junction defining aregion with a raised floor within the fluid channel that facilitatesacceleration of the section from the fluid channel inlet toward thesection-mounting region.
 4. The system of claim 1, wherein thesection-mounting region comprises a base surface having a contouredsurface submerged below a fluid line of fluid within thesection-mounting region, that facilitates mounting of the section thesubstrate, and wherein the section-mounting region is coupled to thefluid channel inlet by a chute that provides downhill flow foracceleration of the section from the fluid channel inlet toward thesection-mounting region.
 5. The system of claim 1, wherein the reservoircomprises a temperature regulating module in contact with fluid from thereservoir, that adjusts a temperature of fluid from the reservoir priorto transmission into the fluid channel.
 6. The system of claim 1,wherein a width dimension of the fluid channel narrows from the fluidchannel inlet to the section-mounting region, thereby facilitatingalignment of the section onto the substrate.
 7. The system of claim 1,further comprising a substrate actuation module proximal thesection-mounting region that transmits the substrate into thesection-mounting region in a first operation, and delivers the substratefrom the section-mounting region, with the section mounted to thesubstrate, in a second operation.
 8. The system of claim 7, furthercomprising a pump coupled to the reservoir and governed by a controller,wherein the controller governs fluid flow from the reservoir into thefluid channel inlet and wherein the substrate actuation modulecoordinates with the controller in mounting the section to thesubstrate.
 9. The system of claim 7, wherein the substrate actuationmodule comprises a grip configured to couple to a surface of thesubstrate, a rail along which the grip translates, and an actuatorconfigured to provide motion of the grip along the rail.
 10. The systemof claim 7, wherein the substrate actuation module is configured torepeatably retract and transmit the substrate into the section-mountingregion for mounting of a set of sections, generated from the bulksample, to the substrate.
 11. The system of claim 1, wherein themanifold comprises a set of openings that direct fluid at an anglerelative to a base surface of the fluid channel inlet, thereby providinga force that separates the section from the blade.
 12. The system ofclaim 1, further including a wrinkle removal module configured totransmit heat toward the section at the section-mounting region, therebyremoving wrinkles from the section.
 13. A method for mounting a sectiononto a substrate, the method comprising: providing a fluid channelhaving a fluid channel inlet and a section-mounting region downstream ofthe fluid channel inlet; receiving the section, from a blade thatgenerates the section from a bulk sample, into the fluid channel inlet;delivering the section from the fluid channel inlet toward thesection-mounting region upon transmission of fluid flow into the fluidchannel inlet, wherein transmission of fluid flow is governed by acontroller; at a substrate actuation module, transmitting the substrateinto the section-mounting region to receive the section, in a firstoperation, in coordination with the controller, thereby placing thesection onto the substrate.
 14. The method of claim 13, whereinreceiving the section at the fluid channel inlet comprises retaining anedge of the section at the blade, and releasing the section into thefluid channel inlet upon delivering fluid flow, through a manifold, thatseparates the section from an adjoining section processed by the blade.15. The method of claim 13, further comprising: at the substrateactuation module, delivering the substrate, with the section mounted tothe substrate, from the section-mounting region in a second operation,in coordination with the controller.
 16. The method of claim 15, whereindelivering the substrate from the section-mounting region, comprisesretracting a grip of the substrate actuation module, with a substratecoupled to the grip; and producing an adhesion force between the sectionand the substrate during retraction of the substrate from thesection-mounting region.
 17. The method of claim 15, whereintransmitting the substrate into the section-mounting region comprisesproviding an interface between the substrate and fluid within thesection-mounting region, receiving the section at the interface, andmodulating a level of fluid within the section-mounting region, therebypromoting positioning of the section at the substrate.
 18. The method ofclaim 13, wherein delivering the section from the fluid channel inlettoward the section mounting region comprises providing a descendingfluid path within the fluid channel, thereby using gravity to facilitateacceleration of the section, positioned at a layer of fluid within thefluid channel, toward the section-mounting region.
 19. The method ofclaim 13, wherein delivering the section from the fluid channel inlettoward the section mounting region comprises providing a progressivelynarrow fluid path within the fluid channel that enables accuratepositioning the section onto the substrate within the section-mountingregion.
 20. The method of claim 12, further comprising transmittingfluid flow through an outlet of the fluid channel into a reservoir influid communication with the fluid channel inlet, and transmitting fluidflow from the reservoir into the fluid channel inlet, thereby deliveringthe section from the blade and into the fluid channel inlet.